Veliparib (1), or 2-[(2R)-2-methyl-2-pyrrolidinyl]-1H-benzimidazole-4-carboxamide, is a poly(ADP-ribose) polymerase (PARP) inhibitor, and is undergoing evaluation in patients with non-small cell lung cancer (NSCLC), breast cancer and ovarian cancer in the United States. Veliparib (1) has the following structural formula:

Scheme 1 depicts a method of preparing Veliparib (1) that is described in WO 2006/110816 A2 and in Penning, T. D. et al. J. Med. Chem. 2009, 52, 514. In this method, carbonyldiimidazole (CDI)-mediated coupling of racemic carbobenzyloxy (Cbz)-protected 2-methylproline (A) with diamine dihydrochloride (B) provides racemic amide (C), which undergoes ring formation upon treatment in refluxing acetic acid to afford racemic benzimidazole (D). Following separation of the (R)- and (S)-enantiomers of racemic benzimidazole (D) by chiral HPLC, the resulting (R)-(D) enantiomer is subjected to deprotection under hydrogenolysis conditions to provide Veliparib (1).

However, the process described in WO 2006/110816 A2 suffers from a number of limitations that reduce its usefulness for large scale manufacturing. For example, the coupling between (Cbz)-protected 2-methylproline (A) and diamine dihydrochloride (B) utilizes a large excess of pyridine, a toxic and odorous solvent. Furthermore, the procedure requires separation of the (R)- and (S)-enantiomers of benzimidazole (D) by chiral HPLC, which not only results in a loss of 50% of the material at an advanced stage of the overall synthesis, also involves use of specialised and costly chiral chromatography columns and equipment that is prohibitive for large scale production. Finally, removal of the Cbz protecting group in the final step by palladium-catalysed hydrogenolysis is disadvantageous because it limits the number of further opportunities to purge the residual transition metal palladium, which must be controlled to very low levels in pharmaceutical products.
A similar process for the preparation of Veliparib (1) is described in Lu, T-X. et al. Chinese Journal of Medicinal Chemistry 2013, 23(6), 476, wherein the use of chiral chromatography to separate late-stage intermediates is replaced by the use of the (R)-enantiomer of 2-methylproline derivative as a starting material. Other approaches to the preparation of Veliparib (1) and analogous compounds, such as those reported in CN 103755595 A and WO 2015139656 A1, also utilize chiral starting materials. However, these methods fail to avoid other problematic aspects of the overall synthesis, such as use of palladium-catalysed hydrogenolysis in the final step to remove the Cbz protecting group, and use of reagents/solvents which are questionable for large scale production, such as excessive pyridine or potentially explosive benzotriazole coupling agents, such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate). A further route to Veliparib (1), reported in CN 106432195 A, avoids the final hydrogenolysis deprotection by employing t-butoxycarbonyl (BOC) as a protecting group, which is removed following benzimidazole formation by treatment with aqueous acetic acid. However, the intermediates used in this process are prepared by the methods of WO 2006/110816 A2, and therefore remain associated with the problems discussed above.
In each of the above cited methods for the preparation of Veliparib (1), the racemic or chiral N-protected 2-methylproline (A) is activated for coupling with diamine (B) using a coupling agent such as CDI or HATU. Another method known for the activation of α-amino carboxylates like 2-methylproline (A) for use in coupling reactions involves formation of an N-carboxyanhydride (NCA) derivative. In Overberger, C. G. et al J. Polym. Sci. Polym. Chem. Ed. 1977, 15, 1413, a procedure is disclosed for the preparation of the NCA derivative (E) of (R)-2-methyl proline having the following formula:

The procedure provided in Overberger et al. involves treatment of N-carbobenzoxy-(R)-2-methylproline with phosphorous pentachloride followed by removal of persistent phosphorous impurities by repeated recrystallization from carbon tetrachloride/n-pentane to afford the NCA derivative in only 25% yield. The use of carbon tetrachloride, classified by ICH (International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Guidance Q3C (R6) as Class 1 (solvents that should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity or their deleterious environmental effect), the necessity for repeated recrystallizations, and the low yield obtained are obvious disadvantages of this approach that limit its widespread use in commercial processes.
Accordingly, a need exists for improved processes for the preparation of Veliparib (1), and the intermediates used in such preparations, that are more amenable to scale-up and use on a commercial scale.